Water-soluble acetaminophen analogs

ABSTRACT

The present invention provides water-soluble acetaminophen prodrugs and formulations which may be suitable for parenteral administration. Methods of treating a disease or condition responsive to acetaminophen (such as fever and/or pain) using the acetaminophen prodrugs, as well as kits, unit dosages, and combinations with additional pharmaceutical agent(s) are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.12/993,088, which is a United States national phase application of PCTApplication No. PCT/US2009/044743 and has an International Filing Dateof May 20, 2009, and claims priority benefit of U.S. ProvisionalApplication No. 61/054,774, entitled “Water-Soluble AcetaminophenAnalogs” filed May 20, 2008, the contents of each of which are herebyincorporated by reference in their entirety as if they were set forth infull below.

BACKGROUND OF THE INVENTION

Acetaminophen (USAN) or paracetamol (INN) (chemically known asN-(4-hydroxyphenyl)acetamide) is an antipyretic and analgesic commonlyused to manage fever of any etiology, minor and severe pains (includingpost-operative pain) and a variety of aches. Acetaminophen is welltolerated and lacks many of the undesired effects of other analgesics,such as non-steroidal anti-inflammatory drugs (NSAIDs) or types ofcyclooxygenase (COX) inhibitors (e.g., stomach lining irritation,adverse effects on platelets and renal function, fetal ductus aiteriousclosure complications and Reye's syndrome)

Acetaminophen has also been shown to be effective in protecting tissuesfrom ischemic damage (i.e. damage caused by ischemia as well asreperfusion that follows ischemia). In guinea pigs, acetaminophen wasrecently found to decrease apoptosis in myocytes, which were subjectedto low-flow global myocardial ischemia for 30 minutes followed by 60minutes of reperfusion (See Am J Physiol Heart Circ Physiol 293:H3348-H3355, 2007). In another study, acetaminophen was found to inhibitboth lipid peroxidation and superoxide anion generation, resulting inretained structural integrity of the rat hippocampus insulted withquinolinic acid in a cerebral ischemia model (See Metabolic BrainDisease 21 (2-3): 180-190, 2006). As with its analgesic applications, animpoliant element of the treatment of ischemic diseases withacetaminophen is the speed at which therapeutic intervention and peaktherapeutic blood concentration occurs.

Opioids have gained widespread use in the clinical setting (for example,to control post-operative pain) due to their excellent analgesicproperties and onset of action. However, the use of certain opioids isoften accompanied by significant adverse side effects (e.g., respiratorydepression, biliary spasm, constipation, sedation, addiction and abusepotential and post-operative nausea and vomiting, etc.) which make themless desirable. The alternative use of NSAIDs, however, impairs bloodclotting (in addition to the side effects previously mentioned), whichis highly undesirable in post-operative settings which require activewound healing and blood clotting. Due to the undesirable qualities ofcertain NSAIDs, COX inhibitors, and. opioids, particularly in certainclinical settings, there has been a need to develop effectiveformulations of acetaminophen.

Parenteral formulations of acetaminophen (e.g., intravenousformulations) would be particularly useful in clinical settings.Compared to oral formulations, an acetaminophen parenteral dosage form,such as intravenous bolus or subcutaneous injection, would have varioustherapeutic advantages. For instance, parenteral acetaminophen may haverelatively faster onset of action and ease of administration in settingssuch as post surgical recovery and trauma. Additionally, as theacetaminophen has a relatively sholi half-life (about 2 hours; seeGoodman and Gillman's The Pharmacological Basis of Therapeutics 10th ed,McGraw-Hill 2001, p 704), parenterally-administered acetaminophen may beprovided at a lower dosage than oral acetaminophen, since much of theorally-administered acetaminophen is cleared from the body beforereaching peak blood concentrations.

Despite a desire for an acetaminophen dosage foam suitable forparenteral administration, development of effective therapeuticacetaminophen beyond oral dosage forms has been limited. A major harrierto developing a parenteral dosage form has been acetaminophen's lowwater solubility (about 1.3 g per 100 mL). To address acetaminophen'sinherent solubility, U.S. Pat. No. 4,322,410 discloses a novel watersoluble phosphate derivative of acetaminophen (4-acetamidophenyldihydrogen phosphate), which has a reported water solubility of 50 g per100 mL of water. However, this acetaminophen derivative is reportedlynot readily amenable to chemical and/or enzymatic hydrolysis and thusriot amenable to clinical use) as it requires alkaline phosphatase andabout 15 hours in vitro to yield the desired acetaminophen drug from thederivative (see Chemical and Pharmaceutical Bulletin 29 (2): 577-580,1981). Other phosphate-containing prodrugs have been disclosed in, forexample, U.S. Pat. Nos. 4,322,410; 5,985,856; 6,204,257; 6,451,776;6,872,838; and 7,244,718; and U.S. patent application Ser. No.11/999,660 (US2008/0318905), filed Dec. 5, 2007.

An ester prodrug of acetaminophen, Propacetarnol® (4-acetamidophenyl2-(diethylamino)acetate) was developed in Europe and was later shown tohave an inferior local tolerance profile when compared to acetaminophen(90% vs 52%, British Journal of Anaesthesia 94 (5): 642-648, 2005; 49%vs 0%, Anesthesia and Analgesia 101; 90-96, 2005). Another acetaminophenproduct marketed in Europe, Perfalgan®, is a large-volume (100-mL)intravenous formulation of acetaminophen for infusion over a relativelylong period (about 15 minutes). These products are not optimal clinicalsolutions either because of their tolerance profile or administrationrequirements.

Thus, there is still a clear need for improved acetaminophen type drugs,such as an acetaminophen prodrug, which are suitable for small-volumeparenteral administration.

The disclosures of all publications, patents, patent applications andother references referred to herein are hereby incorporated herein byreference in their entireties.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention provides a compound of the formula(I):

or a pharmaceutically acceptable salt thereof or solvate of theforegoing. In some embodiments, the compound is in the form of adisodium salt or solvate thereof.

In some embodiments, the invention embraces a formulation comprising thecompound of formula (I) and a carrier. In some embodiments, theformulation comprises an effective amount of the compound of formula (I)and a carrier. In some of these embodiments, the carrier is apharmaceutically acceptable carrier, such as a carrier that is amenableto parenteral administration.

In some embodiments, the invention embraces a formulation comprising thecompound of formula (I) and an opioid, a non-steroidal anti-inflammatorydrug (NSAID), a benzodiazepine, and/or a barbiturate. In someembodiments, the invention embraces a formulation comprising thecompound of formula (I) and codeine, morphine, hydrocodone,hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen, naproxen,caffeine, tramadol, dextropropoxyphene, methylhexital, diazepam,lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen, etodolac,diclofenac, oprostol, meloxicam, piroxicam, doxylamine, pamabrom,carisoprodol, and/or butalbital.

In some embodiments, the invention embraces a substantially pure form ofthe compound of formula (I).

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to acetaminophen (e.g., pain,fever, inflammation, ischemic injury (such as myocardial and/orcerebral), neuronal injury, etc.) comprising administering to anindividual an effective amount of the compound of formula (I) or apharmaceutically acceptable salt thereof or solvate of the foregoing. Insome embodiments of the method, the compound is administeredparenterally. In some embodiments, the compound is administeredintravenously. In some embodiments, the compound is administeredintramuscularly. In some embodiments, the compound is administeredsubcutaneously.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to acetaminophen (e.g., pain,fever, inflammation, ischemic injury (such as myocardial and/orcerebral), neuronal injury, etc.) comprising administering to anindividual a formulation of the compound of formula (I) or apharmaceutically acceptable salt thereof or solvate of the foregoing.

In another aspect, the present invention provides methods of delayingthe onset of acetaminophen action in an individual, the methodscomprising administering to the individual an effective amount of aneffective amount of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof or solvate of the foregoing, wherein thecompound provides a slower onset of acetaminophen action as compared toacetaminophen.

In another aspect, the present invention provides methods of prolongingacetaminophen activity in an individual, the methods comprisingadministering to the individual an effective amount of the compound offormula (I) or a pharmaceutically acceptable salt thereof or solvate ofthe foregoing, wherein the compound provides prolonged acetaminophenactivity as compared to acetaminophen.

In some embodiments, the compound of formula (I) is administered in adosage of about 300 mg to about 2.6 g. In other embodiments, thecompound is administered in a dosage about 1.3 g to about 1.9 g. In someof these embodiments, the volume of the dosage is about 1-25 mL. In someof these embodiments, the volume of the dosage is about 10-20 mL. Insome embodiments, the volume of the dosage is about 1-10 mL. In someembodiments, the volume of the dosage is about 5-10 mL. In some of theseembodiments, the dosage is administered more than once a day. In otherembodiments, the dosage is administered once every other day or less.

In another aspect, methods of administering low volume/highconcentration formulations are provided where the formulations comprisea compound of formula (I) and wherein the compound exhibits enhancedsolubility (e.g., water solubility) as compared to the solubility of theacetaminophen. Low volume/high concentration formulations are alsoprovided herein, such as formulations comprising a compound of formula(I) and a pharmaceutically acceptable carrier. A “low volume/highconcentration” formulation intends a formulation comprising a carrierand prodrug where a given volume of carrier contains a higher molarconcentration of prodrug than is available or obtainable usingacetaminophen. Taking the compound of formula (I) as an example, a lowvolume/high concentration of such prodrug intends a formulationcomprising a carrier and the prodrug wherein the formulation contains ahigher molar concentration of prodrug in a given volume of carrier thanis available or obtainable using acetaminophen. Methods of providing lowvolume/high concentrations of acetaminophen are also provided comprisingadministering to an individual a low volume/high concentrationformulation of a prodrug as detailed herein (e.g., a prodrug of formula(I) or a salt thereof or solvate of the foregoing). In one aspect, themethods entail administering a prodrug that results in rapid release ofacetaminophen when administered to an individual (e.g., by enzymaticcleavage or hydrolysis). Also provided are methods of providing a singledose of acetaminophen in an amount that exceeds currently availabledoses by administering a prodrug as detailed herein.

In another aspect is provided the use of a compound of formula (I) or apharmaceutically acceptable salt thereof or solvate of the foregoing forthe manufacture of a medicament for the treatment of a conditionresponsive to acetaminophen. In another aspect is provided the use of acompound of formula or a pharmaceutically acceptable salt thereof orsolvate of the foregoing for the treatment of a condition responsive toacetaminophen. In some variations, the condition is pain, fever,inflammation, ischemic injury, or neuronal injury.

In another aspect, the present invention provides a kit comprising thecompound of formula (I) or a pharmaceutically acceptable salt thereof orsolvate of the foregoing, and instructions for use. In some embodiments,the instructions relate to the use of the compound of formula (I) forthe treatment or prevention of a disease or condition that is responsiveto acetaminophen (e.g., pain, fever, inflammation, ischemic injury (suchas myocardial and/or cerebral), or neuronal injury.

In another aspect, the present invention provides a kit comprising aformulation of the compound of formula (I) and instructions for use. Insome embodiments, the instructions relate to the use of the compound offormula (I) for the treatment or prevention of a disease or conditionthat is responsive to acetaminophen (e.g., pain, fever, inflammation,ischemic injury (such as myocardial and/or cerebral), or neuronalinjury).

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the formation of acetaminophen from 15 μg/mL prodrug inhuman plasma.

FIG. 2 shows the formation of acetaminophen from 0.3 μg/mL prodrug inhuman plasma.

FIG. 3 shows the pharmacokinetic profile of acetaminophen in rats withtime-dependent plasma concentration of the compound of formula (I)compared to the parent drug acetaminophen.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides acetaminophen prodrugs which have one ormore improved properties (such as increased water solubility and/oronset of action) over existing therapies, which make them potentiallyuseful in low-volume/high-concentration parenteral administration, e.g.,intravenous injections. These compounds may be particularly suitable forrapid treatment of a disease or condition that is responsive toacetaminophen, such as pain, fever, inflammation, ischemic injury (suchas myocardial and/or cerebral), or neuronal injury.

Accordingly, the present invention in one aspect provides theacetaminophen prodrug, (4-acetamidophenoxy)methyl phosphate, or apharmaceutically acceptable salt thereof or solvate of the foregoing.

In another aspect, the present invention provides methods of treating adisease or condition that is responsive to acetaminophen (e.g., pain,fever, inflammation, ischemic injury (such as myocardial and/orcerebral), or neuronal injury, etc.) using the acetaminophen prodrugsdescribed herein.

Also provided are kits, formulations, and unit dosage forms of theprodrug.

Abbreviations and Definitions

Nomenclature of some compounds described herein may be identified usingChemDraw Ultra Version 10.0, available from CambridgeSoft®.

The term “prodrug” refers to a compound which provides an activecompound following administration to the individual in which it is used,by a chemical and/or biological process in vivo (e.g., by hydrolysisand/or an enzymatic conversion). The prodrug itself may be active, or itmay be relatively inactive, then transformed into a more activecompound. The invention embraces prodrugs of acetaminophen as describedherein.

As used herein, “delaying the onset” or “delayed onset” refers to theincreased time to onset of action provided by an acetaminophen prodrugas compared to administration of the molar equivalent of acetaminophenwithin the same time period through the same route of administration.For example, the delayed release of acetaminophen from the prodrug(4-acetamidophenoxy)methyl dihydrogen phosphate may result in delayedsystemic exposure to acetaminophen as compared to administration of themolar equivalent of acetaminophen to an individual.

As used herein, “prolonging activity” or “prolonged activity” refers tothe sustained action provided by an acetaminophen prodrug by virtue ofthe time required to release or otherwise generate acetaminophen fromthe prodrug. For example, administration of the acetaminophen prodrug(4-acetamidophenoxy)methyl dihydrogen phosphate may result in sustainedrelease of acetaminophen as compared to administration of the molarequivalent of acetaminophen over the same time period through the sameroute of administration. “Sustained release” refers to release of theacetaminophen, at a rate such that the blood concentration of theacetaminophen (or metabolite thereof) in an individual is maintained ator within the therapeutic range (e.g., above the minimum effectiveanalgesic concentration but below toxic levels) for an extendedduration. The extended duration in this context intends any time greaterthan the time that the molar equivalent of corresponding acetaminophen,administered through the same route, results in an acetaminophen (ormetabolite thereof) blood concentration within the therapeutic range,

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: 1) is stable to the projected reactions forwhich protection is desired; 2) is removable from the protectedsubstrate to yield the desired functionality; and 3) is removable byreagents compatible with the other functional group(s) present orgenerated in such projected reactions. Selection of suitable protectinggroups for use in the methods described herein is within the ordinaryskill level in the art. Examples of suitable protecting groups can befound in Greene et al. (2006) PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,4th Ed. (John Wiley & Sons, Inc., New york), the content of which isincorporated by reference herein. A “hydroxy protecting group” as usedherein denotes a group capable of protecting a free hydroxy group togenerate a “protected hydroxyl” which, subsequent to the reaction forwhich protection is employed, may be removed without disturbing theremainder of the compound. Exemplary hydroxy protecting groups include,but are not limited to, ethers (e.g., allyl, triphenylmethyt (trityl orTr), benzyl, p-methoxybenzyl (PMB), p-methoxyphenyl (PMP)), acetals(e.g., methoxymethyl (MOM), 3-methoxyethoxymethyl (MEM),tetrahydropyranyl (THP), ethoxy ethyl (EE), methylthiomethyl (MTM),2-methoxy-2-propyl (MOP), 2-trimethylsilylethoxymethyl (SEM)), esters(e.g., benzoate (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate(Troe), 2-trimethylsilylethyl carbonate), silyl ethers (e.g.,trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),triphenylsilyl (TPS), tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyt (TBDPS) and the like.

As used herein, “treatment”, “treating”, or “treat” is an approach forobtaining beneficial or desired results, including clinical results. Forpurposes of this invention, beneficial or desired results include, butare not limited to, one or more of the following: decreasing one or moresymptoms of a disease or condition that is responsive to acetaminophen,diminishing the extent of the disease or condition, stabilizing thedisease or condition (e.g., preventing or delaying the worsening of thedisease or condition), delaying or slowing the progression of thedisease or condition, ameliorating the disease state or condition,decreasing the dose of one or more other medications required to treatthe disease or condition, and increasing the quality of life of anindividual who has been or is suspected of having a disease or conditionthat is responsive to acetaminophen. The disease or condition may be onethat is or is believed to be responsive to acetaminophen (e.g., adisease or condition that is accompanied by a fever and/or pain). Thedisease or condition may be accompanied by inflammation. The disease orcondition may be ischemic injury. The disease or condition may be aneuronal injury. In one variation the condition is post-surgical painand/or fever. In some embodiments, the acetaminophen prodrug and/orformulation comprising the acetaminophen prodrug reduces the severity ofone or more symptoms associated with a disease or condition that isresponsive to acetaminophen by at least about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the correspondingsymptom in the same subject prior to treatment or compared to thecorresponding symptom in other subjects not receiving the acetaminophenprodrug and/or formulation. “Responsive to acetaminophen” as used hereinrefers to a disease or condition, and/or symptom of a disease orcondition which may be treated with acetaminophen.

As used herein, “delaying” means to defer, hinder, slow, retard,stabilize, and/or postpone development of the disease or condition thatis responsive to acetaminophen, and/or one or more symptoms of a diseaseor condition that is responsive to acetaminophen. This delay can be ofvarying lengths of time, depending on the history of the disease and/orindividual being treated. As is evident to one skilled in the art, asufficient or significant delay can, in effect, encompass prevention, inthat the individual does not develop the disease or condition. A methodthat “delays” development of a disease or condition that is responsiveto acetaminophen is a method that reduces the probability of disease orcondition development in a given time frame and/or reduces the extent ofthe disease or condition in a given time frame, when compared to notusing the method. Such comparisons are typically based on clinicalstudies, using a statistically significant number of subjects.

As used herein, an “at risk” individual is an individual who is at riskof developing a disease or condition that is responsive to acetaminophen(e.g., pain, fever, inflammation, ischemic injury (such as myocardialand/or cerebral), or neuronal injury). An individual “at risk” may ormay not have a detectable disease or condition, and may or may not havedisplayed symptoms associated with a detectable disease or conditionprior to the treatment methods described herein. “At risk” denotes thatan individual has one or more so-called risk factors, which aremeasurable parameters that correlate with development of a disease orcondition. An individual having one or more of these risk factors has ahigher probability of developing the disease or condition than anindividual without these risk factor(s).

As used herein, “pharmaceutically acceptable” refers to a material thatis not biologically or otherwise undesirable, e.g., the material may beincorporated (e.g., at the time of manufacturing or administration) intoa pharmaceutical composition administered to an individual withoutcausing any significant undesirable biological effects or interacting ina deleterious manner with any of the other components of the compositionin which it is contained. As used herein, the term “pharmaceuticallyacceptable carrier,” refers to, for example, solvents, stabilizers,pH-modifiers, tonicity modifiers, adjuvants, binders, diluents, etc.,known to the skilled artisan that are suitable for administration to anindividual (e.g., a human). Combinations of two or more carriers arealso contemplated in the present invention. The pharmaceuticallyacceptable carrier(s) and any additional components, as describedherein, should be compatible for use in the intended route ofadministration (e.g., oral, parenteral) for a particular dosage form.Such suitability will be easily recognized by the skilled artisan,particularly in view of the teaching provided herein. Pharmaceuticallyacceptable carriers or excipients have preferably met the requiredstandards of toxicological and manufacturing testing and/or are includedon the Inactive Ingredient Guide prepared by the U.S. Food and Drugadministration.

The term, “effective amount,” as used herein refers to an amount thatresults in a desired pharmacological and/or physiological effect in anindividual who has or is suspected of having (e.g., based on symptomsand/or an individual's perceptions/feelings) a disease or condition orwho displays one or more of its symptoms. An effective amount maycompletely or partially prevent the occurrence or recurrence of thedisease or condition or symptom thereof and/or may be therapeutic interms of a partial or complete cure for the disease or condition and/oradverse effect attributable to the disease or condition (e.g., pain). Inreference to a disease or condition described herein (e.g., pain), aneffective amount may comprise an amount sufficient to, among otherthings, reduce and/or relieve to some extent one or more of the symptomsassociated with a disease or condition that is responsive toacetaminophen (e.g., pain, fever, inflammation, ischemic injury (such asmyocardial and/or cerebral), or neuronal injury). In certainembodiments, the effective amount is sufficient to prevent thecondition, as in being administered to an individual prophylactically.Effective amount includes the eradication or amelioration of theunderlying condition being treated and/or eradication or amelioration ofone or more of the symptoms associated with the underlying conditionsuch that the individual reports an improvement in feeling or condition(e.g., decreased pain intensity and/or duration), notwithstanding thatthe individual may still be afflicted with the underlying disease orcondition. Effective amount also includes halting or slowing theprogression of the disease or condition, regardless of whetherimprovement or the disease or condition is realized.

The “effective amount” may vary depending on the composition beingadministered, the condition being treated/prevented (e.g., the type ofpain), the severity of the condition being treated or prevented, theage, body size, weight, and relative health of the individual, the routeand form of administration, the judgment of the attending medical orveterinary practitioner (if applicable), and other factors appreciatedby the skilled artisan in view of the teaching provided herein. Aneffective amount may be assessed, for example, by using data from one ormore clinical, physiological, biochemical, histological,electrophysiological, and/or behavioral evaluations.

As is understood in the art, an “effective amount” may be in one or moredoses, i.e., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more additional pharmaceuticalagents, and an acetaminophen prodrug may be considered to be given in aneffective amount if, in conjunction with one or more additionalpharmaceutical agents, one or more desirable or beneficial result(s) maybe or are achieved.

When used with respect to methods of treatment and/or prevention and theuse of the acetaminophen prodrugs thereof described herein, anindividual “in need thereof” may be an individual who has been diagnosedwith, previously treated for, and/or suspected of having the disease orcondition to be treated. With respect to prevention, the individual inneed thereof may also be art individual who is at risk for a disease orcondition (e.g., a family history of the condition, life-style factorsindicative of risk for the condition, etc.).

In some variations, the individual has been identified as having one ormore diseases or conditions, and/or symptoms thereof described herein.Identification of the diseases or conditions and/or symptoms thereof bya skilled physician is routine in the art (e.g., detection of allergies,cold, cough, flu, pain, etc.) and may also be suspected by theindividual or others, for example, due to pain, fever, etc.

In some embodiments, the individual has been identified as susceptibleto one or more of the diseases or conditions as described herein. Thesusceptibility of an individual may be based on any one or more of anumber of risk factors and/or diagnostic approaches appreciated by theskilled artisan, including, but not limited to, genetic profiling,family history, medical history (e.g., appearance of relatedconditions), lifestyle or habits.

In some embodiments, the individual is a mammal, including, but notlimited to, bovine, horse, feline, rabbit, canine, rodent, or primate.In some embodiments, the mammal is a primate. In some embodiments, theprimate is a human. In some embodiments, the individual is human,including adults, children, infants, and preemies. In some embodiments,the individual is a non-mammal. In some variations, the primate is anon-human primate such as chimpanzees and other apes and monkey species.In some embodiments, the mammal is a farm animal such as cattle, horses,sheep, goats, and swine; pets such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice, and guineapigs; and the like. In some embodiments, the individual is a non-mammal,including, but not limited to, birds, and the like. The term“individual” does not denote a particular age or sex.

As used herein, “combination therapy” means a first therapy thatincludes an acetaminophen prodrug in conjunction with a second therapy(e.g., surgery and/or an additional pharmaceutical agent) useful fortreating, stabilizing, preventing, and/or delaying the disease orcondition. Administration in “conjunction with” another compoundincludes administration in the same or different composition(s), eithersequentially, simultaneously, or continuously, through same or differentroutes. In one variation, the combination therapy may include anacetaminophen prodrug and acetaminophen. In some embodiments, thecombination therapy optionally includes one or more pharmaceuticallyacceptable carriers or excipients, non-pharmaceutically activecompounds, and/or inert substances.

As used herein, the term“additional pharmaceutical agent,” refers to anactive agent other than the acetaminophen prodrug (e.g., another drugand/or acetaminophen itself) which is administered to elicit atherapeutic effect. The additional pharmaceutical agent(s) may bedirected to (1) a therapeutic effect related to the disease or conditionthat acetaminophen prodrug is intended to treat or prevent (e.g., pain),(2) treat or prevent a symptom of the underlying condition, (3) reducethe appearance or severity of side effects of administering theacetaminophen prodrug, and/or (4) a therapeutic effect related to adisease or condition that is not responsive to acetaminophen or isrelatively less responsive to acetaminophen (e.g., insomnia, anxiety,depression,inflammation, nausea, and/or vomiting).

Reference to “about” a value or parameter herein includes (anddescribes) variations that are directed to that value or parameter perse. For example, a description referring to “about X” includes thedescription of “X”.

As used herein and in the appended claims, the singular forms “a, ”“or,” and “the” include plural referents unless the context clearlydictates otherwise. It is understood that aspect and variations of theinvention described herein include “consisting” and/or “consistingessentially of” aspects and variations.

Unless defined otherwise or clearly indicated by context, all technicaland scientific terms and abbreviations used herein have the same meaningas commonly understood by one of ordinary skill in the art to which thisinvention belongs.

Acetaminophen Prodrugs

The invention embraces acetaminophen prodrugs which may be useful in thetreatment of a disease or condition that is responsive to acetaminophen.In some embodiments, the acetaminophen prodrugs contain a phosphategroup linked to the acetaminophen hydroxyl group via a linker. In someembodiments, the linker is an alkylene linker (e.g., methylene). In someembodiments of the present invention, acetaminophen prodrug is of theformula:

In some embodiments, the acetaminophen prodrug is of the formula:

In some embodiments, the acetaminophen prodrug is in substantially pureform. Unless otherwise stated, “substantially pure” intends apreparation of the prodrug that contains no more than 15% impurity,wherein the impurity denotes compounds other than the acetaminophenprodrug and acetaminophen alone, but does not include acetaminophenand/or other forms or the prodrug (e.g., different salt or non-saltversions of the prodrug). In one variation, a preparation ofsubstantially pure prodrug is provided wherein the preparation containsno more than 25% impurity, or no more than 20% impurity, or no more than10% impurity, or no more than 5% impurity, or no more than 3% impurity,or no more than 1% impurity, or no more than 0.5% impurity.

The invention also embraces all of the solvate, hydrate and/or salt(e.g., pharmaceutically acceptable salt) forms of the acetaminophenprodrugs described herein and methods of using the same. In someembodiments, the acetaminophen prodrugs of the present invention canexist in unsolvated forms as well as solvated forms (i.e., solvates).The acetaminophen prodrugs may also include hydrated forms (i.e.,hydrates).

The invention embraces all salts of the compounds described herein, aswell as methods of using such salts of the compounds. The invention alsoembraces all non-salt forms of any salt of a compound described herein,as well as other salts of any salt of a compound named herein. In someembodiments, the salts of the compounds are pharmaceutically acceptablesalts. “Pharmaceutically acceptable salts” are those salts which retainthe biological activity of the free compounds and which can beadministered as drugs or pharmaceuticals to an individual (e.g., ahuman). In some embodiments, the acetaminophen prodrugs are mono- ordi-substituted by alkali metal or alkaline earth metals. In someembodiments, the acetaminophen prodrug is a mono alkaline phosphate salt(e.g., mono sodium phosphate salt). In some embodiments, theacetaminophen prodrug is a di-alkaline phosphate salt (e.g., disodiumphosphate salt). The desired salt of a basic functional group of acompound may be prepared by methods known to those of skill in the artby treating the compound with an acid. The desired salt of an acidicfunctional group compound can be prepared by methods known to those ofskill in the art by treating the compound with a base. Examples ofinorganic salts of acid compounds include, but are not limited to,alkali metal and alkaline earth salts, such as sodium salts, potassiumsalts, magnesium salts, bismuth salts, and calcium salts; ammoniumsalts; and aluminum salts. Examples of organic salts of acid compoundsinclude, but are not limited to, procaine, dibenzylamine,N-ethylpiperidine, N,N′-dibenzylethylenediamine, trimethylamine, andtriethylamine salts.

In some embodiments, the acetaminophen prodrugs exhibit enhancedsolubility when compared to acetaminophen. For instance, the solubilityof acetaminophen in water at room temperature is about 13 mg/mL, whereasthe solubility of (4-acetamidophenoxy)methyl phosphate and sodium(4-acetamidophenoxy)methyl phosphate in water at room temperature isapproximately 145 mg/mL and 160 mg/mL, respectively. In someembodiments, the acetaminophen prodrugs exhibit reduced or nobioactivity or reduced or no affinity for a receptor whereverapplicable, when compared to acetaminophen.

The acetaminophen prodrugs described herein may be relatively stableunder some conditions (e.g., during storage and/or preparation in asaline solution), while being converted to their parent drugs underother conditions (e.g., following introduction into an in vitro or invivo system, such as administration into an individual). In someembodiments, the prodrug (e.g., a prodrug of formula I or II at, forexample, about 0.3 ng/mL or about 15 ng/mL in plasma, or between about0.3 ng/mL or about 15 ng/mL in plasma) is capable of greater than 10%,or 15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 60%,or 75% conversion to acetaminophen after about any of 1 min, 5 min, 10min, 15 min, 20 min, or 30 min, or 45 min, or 1 hr at 37° C. In someembodiments, the prodrug (e.g., a prodrug of formula I or II at, forexample, about 0.3 ng/mL or about 15 ng/mL in human plasma, or betweenabout 0.3 ng/mL or about 15 ng/mL in human plasma) is capable of greaterthan about 30%, or about 45% conversion to acetaminophen after about 1hr at 37° C. In some of these embodiments, the acetaminophen prodrugsare not capable of said conversion to acetaminophen in water, propyleneglycol and/or saline at room temperature. For example, in some of theseembodiments, the prodrug is not capable of more than any of about 5%, or10%, or 20%, or 25%, or 30% or 40%, or 60%, or 70% conversion to parentdrug at 30 min or 60 min in water or propylene glycol at roomtemperature. In one embodiment, the acetaminophen prodrug of formula Ior II at a concentration of about 15 ng/mL in human plasma (or 0.3ng/mL, or between 0.3 ng/mL and 15 ng/mL) at 37° C. is capable ofgreater than 30% conversion to the parent drug at 45 min, and is notcapable at the same concentration in water at room temperature of morethan 30% conversion at 45 min. In some embodiments, the prodrug (e.g.,the acetaminophen prodrug of formula I or II) is capable of at leastabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%increased conversion to parent drug in human plasma at 37° C. comparedto water at room temperature after the same time of exposure.

Synthetic Methods

The compounds of the invention may be prepared using a number of methodsfamiliar to one of skill in the art. The discussion below is offered toillustrate one method available for use in assembling the compounds ofthe invention and is not intended to limit the scope of the reactions orreaction sequences and/or conditions that are useful in preparingcompounds of the invention.

Target compounds of the invention may be synthesized staiiing withreadily available acetaminophen as shown in Scheme I below.

As shown in Scheme I, treatment of acetaminophen with sodium hydridefollowed by chloromethyl methyl sulfide generates the correspondingthioether, which may be converted to the protected phosphate with theaddition of a di-protected phosphate, such as dibenzyl phosphate ordi-tert-butyl phosphate, in the presence of a halogenating agent (suchas N-iodo succinimide (NIS) or N-bromo succinimide (NBS)). Deprotectionunder reducing conditions, followed by conversion to the desired salt,such as a sodium salt, results in sodium (4-acetamidophenoxy)methylphosphate. Any suitable protecting group and accompanying conditions fordeprotection may be employed.

The invention also embraces methods of preparing the prodrugs describedherein. In one, aspect is provided a process for preparing a compound offormula (I):

comprising

-   (a) reacting a compound formula SI-A:

or a pharmaceutically acceptable salt thereof or solvate of theforegoing, with halomethyl sulfide in a suitable solvent;

-   (b) reacting the compound formed from step (a), or a    pharmaceutically acceptable salt thereof or solvate of the    foregoing, with a di-protected phosphate in suitable solvent; and-   (c) deprotection of the di-protected phosphate of the compound    formed from step (b).

In some embodiments of step (a) for the process for preparing a compoundof formula I, the halomethyl sulfide is chloromethyl methyl sulfide. Insome embodiments of step (a), the suitable solvent is HMPA. In someembodiments of step (a), the reaction further comprises NaH. In someembodiments of step (b) for the process for preparing a compound offormula I, the di-protected phosphate is di-tert-butyl phosphate ordibenzylphosphate. In some embodiments of step (b), the suitable solventis THF. In some embodiments of step (b), the reaction further comprisesNIS or NBS. In some embodiments of step (c) for the process forpreparing a compound of formula I, the deprotection comprises reducingconditions. In some embodiments of step (c), the deprotection comprisesusing Pd(0Hh/H₂. In some embodiments of step (c), the deprotectioncomprises acidic conditions. In some embodiments of step (c), thedeprotection comprises treatment with acetic acid. In some embodimentsof step (c), the suitable solvent is a protic solvent (e.g., methanol).

Formulations

The acetaminophen prodrugs described herein can be in formulations(including pharmaceutical compositions) with additives such asexcipients (e.g., one or more excipients), antioxidants (e.g., one ormore antioxidants stabilizers (e.g., one or more stabilizers),preservatives (e.g., one or more preservatives), pH adjusting andbuffering agents (e.g., one or more pH adjusting and/or bufferingagents), tonicity adjusting agents (e.g., one or more tonicity adjustingagents), thickening agents (e.g., one or more thickening agents),suspending agents (e.g., one or more suspending agents), binding agents(e.g., one or more binding agents, viscosity-increasing agents (e.g.,one or more viscosity-increasing agents), and the like, either alone ortogether with one or more additional pharmaceutical agents, providedthat the additional components are pharmaceutically acceptable for theparticular disease or condition to be treated. In some embodiments, theformulation may include combinations of two or more of the additionalcomponents as described herein (e.g., 2, 3, 4, 5, 6, 7, 8, or moreadditional components). In some embodiments, the additives includeprocessing agents and drug delivery modifiers and enhancers, such as,for example, calcium phosphate, magnesium stearate, talc,monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose,hydroxypropyl-f3-cyclodextrin, polyvinylpyrrolidinone, low meltingwaxes, ion exchange resins, and the like, as well as combinations of anytwo or more thereof. Other suitable pharmaceutically acceptableexcipients are described in REMINGTON's PHARMACEUTICAL SCIENCES, MarekPub. Co., New Jersey 18th edition (1996), and REMINGTON: THE SCIENCE ANDPRACTICE OF PHARMACY, Lippincott Williams & Wilkins, Philadelphia, 20thedition (2003) and 21st edition (2005).

The formulations may vary or be tailored according to the condition tobe treated, the amount of compound to be administered, the condition ofthe individual, and other variables that will readily be apparent to oneof ordinary skill in the art in view of the teachings provided herein.

In some embodiments, the formulation (e.g., formulations amenable toparenteral administration) is an aqueous formulation with a pH fromabout 3.5 to about 9.5, or from about 4.5 to about 8.5, or from about5.0 to about 9.0, or from about 5.5 to about 8.5, or from about 6.0 toabout 8.0, or from about 6.5 to about 8.0, or from about 7.0 to about8.0, or about 7.4.

Formulations comprising a prodrug of the formula I or II and saline areprovided. In one aspect, such formulations are at physiological pH(about 7.4). Such formulations may be amenable to storage and subsequentuse with the prodrug remaining intact for prolonged periods of time(e.g., during storage) and converted to acetaminophen afteradministration to an individual (e.g., an adult, child, or infant). Insome embodiments, the prodrug is stored as a dry powder and theformulation is generated by dissolving the dry powder in saline prior toadministration. In one aspect, prodrug formulations are provided, e.g.,formulations comprising the molar equivalent of about any of 50 mg/mL,75 mg/mL, 100 mg/mL, 125 mg/mL, 150 mg/mL, 175 mg/mL, or 200 mg/mL ofacetaminophen, wherein molar equivalent is the amount of prodrug thatwould result in the indicated amount of acetaminophen upon completeconversion. For any amount (e.g., dosage) of prodrug described herein,also contemplated is the molar prodrug equivalent for that amount ofacetaminophen. Single bolus formulations are also provided, e.g., up toabout any of 5 mL, 10 mL, or 15 mL (at, for example, the molar prodrugequivalent of about 1450 mg to about 1600 mg of acetaminophen).

Kits

The invention also provides kits containing materials useful for thetreatment or prevention of a condition that is responsive toacetaminophen (e.g., pain). The kits may contain an acetaminophenprodrug of the invention and instructions for use. The kits may comprisea container with a label. Suitable containers include, for example,bottles, vials, and test tubes. The containers may be formed from avariety of materials such as glass or plastic. The containers may holdan acetaminophen prodrug or a formulation of an acetaminophen prodrug(e.g., a formulation further comprising one or more additionalpharmaceutical agents). The label on the container may indicate that theacetaminophen prodrug or the formulation is used for treating orsuppressing a condition that is responsive to acetaminophen (e.g.,pain), and may also indicate directions for either in vivo or in vitrouse, such as those described herein.

The invention also provides kits comprising one or more of theacetaminophen prodrugs of the invention. In some embodiments, the kit ofthe invention comprises the container described above. In otherembodiments, the kit of the invention comprises the container describedabove and a second container comprising a buffer. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, syringes, andpackage inserts with instructions for performing any methods describedherein.

In other aspects, the kits may be used for any of the methods describedherein, including, for example, to treat an individual with one or moreconditions responsive to acetaminophen (e.g., pain and/or fever), or tosuppress one or more such conditions.

In certain embodiments the kits may include a dosage amount of at leastone formulation as disclosed herein. In one aspect, dosage formscorrespond to dose that exceed the molar equivalent of 4 g/day ofacetaminophen. Kits may also comprise a means for the delivery of theformulation thereof.

The kits may include additional pharmaceutical agents for use inconjunction with the formulation described herein. In some variations,the additional pharmaceutical agent(s) may be one or more analgesicdrug(s). These agents may be provided in a separate form, or mixed withthe compounds of the present invention, provided such mixing does notreduce the effectiveness of either the pharmaceutical agent orformulation described herein and is compatible with the route ofadministration. Similarly the kits may include additional agents foradjunctive therapy or other agents known to the skilled artisan aseffective in the treatment or prevention of the conditions describedherein.

The kits may optionally include appropriate instructions for preparationand/or administration of a formulation comprising an acetaminophenprodrug of the invention. Information detailing possible side effects ofthe formulation, and any other relevant information may also beenclosed. The instructions may be in any suitable format, including, butnot limited to, printed matter, videotape, computer readable disk,optical disc or directions to internet-based instructions.

In another aspect of the invention, kits for treating an individual whosuffers from or is susceptible to a disease or condition describedherein (e.g., pain and/or fever) are provided, comprising a firstcontainer comprising a dosage amount of a composition as disclosedherein, and instructions for use. The container may be any of thoseknown in the art and appropriate for storage and delivery of intravenousformulation. In certain embodiments the kit further comprises a secondcontainer comprising a pharmaceutically acceptable carrier, diluent,adjuvant, etc. for preparation of the formulation to be administered tothe individual.

Kits may also be provided that contain sufficient dosages of thecompounds described herein (including formulations thereof) to provideeffective treatment for an individual for an extended period, such as1-3 days, 1-5 days, a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9months or more.

The kits may include the composition as described herein packaged ineither a unit dosage form or in a multi-use form. The kits may alsoinclude multiple units of the unit dose form.

Methods of Treatment

The acetaminophen prodrugs of the present invention may be used to treata disease or condition that is responsive to acetaminophen (e.g., painand/or fever). In one embodiment, the invention provides a method oftreating a disease or condition that is responsive to acetaminophencomprising administering to an individual an effective amount of anacetaminophen prodrug (e.g., (4-acetamidophenoxy)methyl phosphate orsodium (4-acetamidophenoxy)methyl phosphate). In some embodiments, theindividual is at risk of developing a disease or condition that isresponsive to acetaminophen. In some embodiments, methods of treatingpain, fever, inflammation, ischemic injury (such as myocardial and/orcerebral), or neuronal injury in an individual, comprising administeringto the individual an effective amount of an acetaminophen prodrug (e.g.,(4-acetamidophenoxy)methyl phosphate or sodium acetamidophenoxy)methylphosphate) are provided. In one variation, the individual ispost-operative and has or is believed to have or developedpost-operative pain. In one variation, the prodrug is administeredprophylactically for post-operative pain. In one variation, theindividual is not amenable to oral administration of acetaminophen.

The invention embraces methods of treating pain of any etiology,including acute and chronic pain, and any pain in which acetaminophenanalgesic is prescribed. Examples of pain include post-surgical pain,post-operative pain (including dental pain), migraine, headache andtrigeminal neuralgia, pain associated with burn, wound or kidney stone,pain associated with trauma (including traumatic head injury),neuropathic pain (e.g., peripheral neuropathy and post-herpeticneuralgia), pain associated with musculo-skeletal disorders, strains,sprains, contusions, fractures, such as myalgia, rheumatoid arthritis,osteoarthritis, cystitis, pancreatitis, inflammatory bowel disease,ankylosing spondylitis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism and peri-articular disorders, and painassociated with cancer (including “break-through pain” and painassociated with terminal cancer). Examples of pain with an inflammatorycomponent (in addition to some of those described above) includerheumatic pain, pain associated with mucositis, and dysmenorrhea. Insome vaiiations, the methods and formulations of the present inventionare used for treatment or prevention of post-surgical pain and/or cancerpain. In some variations, the methods and compositions of the presentinvention are used for treatment or prevention of pain that is selectedfrom the group consisting of pain associated with surgery, trauma,osteoarthritis, rheumatoid arthritis, lower back pain, fibromyalgia,postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathyand complex regional pain syndrome.

In some variations, the methods and compositions of the presentinvention (e.g., (4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) are used for treatment orprevention of pain and/or fever (e.g., in adults, children and/orinfants). In some embodiments, the methods and compositions of thepresent invention (e.g., (4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) are used for treatment of pain,such as acute pain (e.g., acute pain following surgery, such asorthopedic surgery of adults, children, and/or infants). In someembodiments, the methods and compositions of the present invention(e.g., (4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) are used for treatment orprevention of fever, such as endotoxin-induced fever (e.g.,endotoxin-induced fever in adults, children, and/or infants). In someembodiments, the methods and compositions of the present invention(e.g., (4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) are used for treatment orprevention of fever in children and/or infants. In some embodiments, thefever is selected front low-grade fever, moderate fever, high-gradefever and hyperpyrexia fever. In some embodiments, the fever is selectedfrom Pel-Ebstein fever, continuous fever, intermittent fever, andremittent fever.

In some embodiments, the invention embraces methods of delaying theonset of acetaminophen action in an individual in need of acetaminophentherapy, the method comprising administering to the individual aneffective amount of an acetaminophen prodrug (e.g.,(4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) wherein the prodrug provides aslower onset of acetaminophen action as compared to acetaminophen. Inone variation, administration of the acetaminophen prodrug (e.g.,(4-acetamidophenoxy)methyl phosphate or sodium(4-acetamidophenoxy)methyl phosphate) delays the onset of parent drugaction by greater than about 5 minutes, or 10 minutes, or 15 minutes, or30 minutes, or 1 hour, or 2, hours, or 3 hours, or 4 hours, or 6 hours,or 8 hours, or 10 hours, or 12 hours, or 18 hours, or 24 hours ascompared to administration of acetaminophen. In some embodiments, theinvention embraces little or no delay in the onset of the parent drug.

In some embodiments, the invention embraces methods of prolongingacetaminophen activity in an individual in need of acetaminophentherapy, the method comprising administering to the individual aneffective amount of an acetaminophen prodrug (e.g.,(4-acetamidophenoxy)methyl phosphate or sodium (4acetamidophenoxy)methylphosphate) wherein the prodrug provides prolonged acetaminophen activityas compared to acetaminophen. In one variation, administration of theacetaminophen prodrug (e.g., (4-acetamidophenoxy)methyl phosphate orsodium (4-acetamidophenoxy)methyl phosphate) prolongs activity bygreater than about 5 minutes, or 10 minutes, or 15 minutes, or 30minutes, or 1 hour, or 2, hours, or 3 hours, or 4 hours, or 6 hours, or8 hours, or 10 hours, or 12 hours, or 18 hours, or 24 hours as comparedto administration of the acetaminophen. In some embodiments, theinvention embraces little or no prolonging of activity compared toadministration of acetaminophen.

In some embodiments, the invention embraces a method of providingacetaminophen to an individual, the method comprising administering anacetaminophen prodrug (e.g., a prodrug of formula I or II), wherein theacetaminophen prodrug converts to acetaminophen. Also provided aremethods of providing acetaminophen to an individual by administering anacetaminophen prodrug (e.g., a prodrug of formula I or II), where theprodrug converts to acetaminophen in vivo. In one aspect, the prodrug(e.g., a prodrug of formula I or II) results in conversion toacetaminophen within about 1, 5, 10, 15, or 30 min followingadministration. Conversion may be measured by techniques known in theart, including those detailed in the Experimental section herein. Insome embodiments, the invention embraces methods of providingacetaminophen to an individual (e.g., an individual in need ofacetaminophen therapy), the method comprising administering to theindividual an effective amount of an acetaminophen prodrug (e.g., aprodrug of formula I or II) wherein greater than about any of 10%, or15%, or 20%, or 25%, or 30%, or 35%, or 40%, or 45%, or 50%, or 60%, or75% or 85%, or 90%, or 95% of the prodrug is converted to acetaminophenafter less than about any of 1 min, 3 min, 5 min, 10 min, 20 min, or 30min, or 45 min, or 1 hr following administration. In some embodiments,the method comprises administering to the individual an effective amountof an acetaminophen prodrug (e.g., a prodrug of formula I or II) whereingreater than about 10% or about 20% of the prodrug is converted toacetaminophen after less than about 1 min or about 3 min followingadministration.

In some embodiments, the invention embraces a method of providingacetaminophen to an individual (e.g., an individual in need ofacetaminophen therapy), the method comprising administering to theindividual (e.g., intravenously) an effective amount of an acetaminophenprodrug (e.g., a prodrug of formula I or II) wherein the resultingconcentration of acetaminophen (e.g., at about any of 10 min, or 20 min,or 30 min, or 45 min, or 1 hr, or 2 hr, or 3 hr followingadministration) is within less than about any of 50%, or 40%, or 30%, or25%, or 20%, or 15%, or 10%, or 5% when compared to the administeringacetaminophen alone under the same conditions. For example, in someembodiments, a methods of providing acetaminophen to an individual inneed of acetaminophen therapy are provided, the methods comprisingintravenously administering to the individual an effective amount of anacetaminophen prodrug (e.g., a prodrug of formula I or II) wherein theresulting concentration of acetaminophen or a metabolite thereof (e.g.,at about 30 min or 1 hr following administration) is within less thanabout 15% or about 5% when compared to administering acetaminophen aloneunder the same conditions.

Combination Therapy

The acetaminophen prodrugs described herein may be formulated and/oradministered in conjunction with one or more additional pharmaceuticalagents, as described herein and as known in the art, including one ormore additional pharmaceutical agents to further reduce the occurrenceand/or severity of symptoms and/or clinical manifestations thereof, aswell as additional pharmaceutical agents that treat or prevent theunderlying conditions, or in conjunction with (e.g., prior to,concurrently with, or after) additional treatment modalities. Theacetaminophen prodrugs as described herein may be administered before,concurrently with, or after the administration of one or more of theadditional pharmaceutical agents. The acetaminophen prodrugs describedherein may also be administered in conjunction with (e.g., prior to,concurrently with, or after) agents to alleviate the symptoms associatedwith either the condition or the treatment regimen.

In some embodiments of the formulations and methods of the presentinvention, the acetaminophen prodrugs are used in combination with oneor more additional pharmaceutical agents. Representative additionalpharmaceutical agents include opioids (natural, semi-synthetic, orsynthetic), non-steroidal anti-inflammatory drugs (NSAIDs),benzodiazepines, barbiturates and other compounds, such as caffeine.Examples of compounds contemplated for combination with prodrug ofcurrent invention include, but are not limited to, codeine, morphine,hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac, ibuprofen,naproxen, caffeine, tramadol, dextropropoxyphene, methylhexital,diazepam, lorazepam, midazolam, propoxyphene, ketoprofen, flurbiprofen,etodolac, diclofenac, misoprostol, meloxicam, piroxicam, doxylamine,pamabrom, carisoprodol, and butalbital.

One potential advantage of a combination formulation is that theformulation may induce analgesia beyond the ceiling effect ofacetaminophen without approaching the toxic or nearly toxic dose levelsof acetaminophen. Combinations of the acetaminophen prodrugs withbenzodiazepines such as diazepam, lorazepam, midazolam or any otherbenzodiazepines, may be used for treatment of pre- and postoperativeanxiety in addition to the treatment of e.g., analgesia. Suchcombination may be particularly useful in dental surgeries (e.g., moleextraction).

The above additional pharmaceutical agents to be employed in combinationwith the acetaminophen prodrugs of the invention may be used intherapeutic amounts, such as those indicated in the PHYSICIANS' DESKREFERENCE (PDR) 53rd Edition (1999), or such therapeutically usefulamounts as would be known to one of ordinary skill in the art.

Additional pharmaceutical agents (e.g., analgesic drugs) administeredwith one or more of the acetaminophen prodrugs of the invention can beadministered at the recommended maximum clinical dosage or at lowerdoses. Dosage levels of the additional pharmaceutical agents in theformulations of the invention may be varied so as to obtain a desiredtherapeutic response depending on the route of administration, severityof the disease and the characteristics and response of the patient. Thecombination can be administered as separate formulations or as a singledosage form containing both agents. When administered as a combination,the acetaminophen prodrugs can be formulated as separate formulations,which are given at the same time or different tunes, or theacetaminophen prodrugs, can be given as a single formulation.

As will be well appreciated by the skilled artisan, for particularconditions, different additional pharmaceutical agent(s) and/oradditional treatment modality(ies) may be employed.

In some embodiments, an acetaminophen prodrug of the current inventionmay be formulated and/or administered with acetaminophen itself. Suchcombination therapy may provide an initial therapeutic amount of theparent drug, followed by a delayed and/or prolonged parent drug activityfrom the prodrug. For example, a combination of(4-acetamidophenoxy)methyl dihydrogen phosphate with acetaminophen mayprovide an initial treatment of pain with acetaminophen, followed byprolonged treatment of pain with the acetaminophen prodrug. Suchformulations may permit a decreased dosing frequency. Alternatively, aninitial dose of prodrug I or II (e.g., as a low volume, highconcentration dose to treat post-operative pain and/or fever) may befollowed by administration of acetaminophen to treat pain and/or fever(e.g., after discharge from a hospital or surgical setting).

The formulations and methods described herein may be used alone or inconjunction with (e.g., prior to, concurrently with, or after) othermodes of treatments (e.g., adjunctive therapy with additionalpharmaceutical agents described herein with reference to pharmaceuticalformulations of the claimed compounds or known to the skilled artisan)used to treat or prevent the condition being treated/prevented and/oradministration of an additional treatment modality, or combinations ofthe foregone). For example, in combination with one or more additionalpharmaceutical agents as described herein and known to those of skill inthe art and/or currently available treatment modalities, including, forexample, surgery or radiotherapy. As used herein, the term “additionaltreatment modality” refers to treatment/prevention of the conditionsdescribed herein without the use of a pharmaceutical agent (e.g.,surgery, radiotherapy, etc.). Where combinations of pharmaceuticalagent(s) and/or additional treatment modality(ies) are used, they maybe, independently, administered prior to, concurrently with, or afteradministration of one or more of the acetaminophen prodrugs (orformulation(s) thereof) as described herein.

The optimal combination of one or more additional treatment modalitiesand/or additional pharmaceutical agents in conjunction withadministration of the formulations described herein, can be determinedby an attending physician or veterinarian based on the individual andtaking into consideration the various factors effecting the particularindividual, including those described herein.

Dosing and Methods of Administration

The acetaminophen prodrugs and formulations described herein willgenerally be used in an amount effective to achieve the intended result,for example in an effective amount to treat or prevent the particularcondition being treated or prevented (e.g., pain and/or fever). Theamount of the acetaminophen prodrug or formulation administered in orderto administer an effective amount will depend upon a variety of factors,including, for example, the particular condition being treated, thefrequency of administration, the particular formulation beingadministered, the severity of the condition being treated and the age,weight and general health of the individual, the adverse effectsexperienced by the individual being treated, etc. Determination of aneffective dosage is within the capabilities of those skilled in the art,particularly in view of the teachings provided herein. Dosages may alsobe estimated using in vivo animal models.

The amount of acetaminophen prodrug that may be combined with thecarrier materials to produce a single dosage form may vary dependingupon the host to which the acetaminophen prodrug is administered and theparticular mode of administration, in addition to one or more of thevariety of factors described above. A pharmaceutical unit dosage chosenmay be fabricated and administered to provide a defined finalconcentration of drug in the blood, tissues, organs, or other targetedregion of the body. The effective amount for a given situation can bereadily determined by routine experimentation and is within the skilland judgment of ordinary clinician.

In some embodiments, the dosage of acetaminophen prodrug required toobtain the same blood level concentration as acetaminophen is lower dueto the increased solubility of the prodrug. In some embodiments, therequired dosage of the prodrug to obtain the same blood levelconcentration as the acetaminophen is 1.2, 2, 5, 7.5, 10, 15, 20, 50, or100 times lower than acetaminophen.

Examples of acetaminophen prodrug dosages (alone or in combination)which can be used are an effective amount within the dosage range ofabout 0.1 μg/kg to about 300 mg/kg, or within about 1.0 μg/kg to about40 mg/kg body weight, or within about 1.0 μg/kg to about 20 mg/kg bodyweight, or within about 1.0 μg/kg to about 10 mg/kg body weight, orwithin about 10.0 μg/kg to about 10 mg/kg body weight, or within about100 μg/kg to about 10 mg/kg body weight, or within about 1.0 mg/kg toabout 10 mg/kg body weight, or within about 10 mg/kg to about 100 mg/kgbody weight, or within about 50 mg/kg to about 150 mg/kg body weight, orwithin about 100 mg/kg to about 200 mg/kg body weight, or within about150 mg/kg to about 250 mg/kg body weight, or within about 200 mg/kg toabout 300 mg/kg body weight, or within about 250 mg/kg, to about 300mg/kg body weight. Other dosages which can be used are about 0.01 mg/kgbody weight, about 0.1 mg/kg body weight, about 1 mg/kg body weight,about 10 mg/kg body weight, about 20 mg/kg body weight, about 30 mg/kgbody weight, about 40 mg/kg body weight, about 50 mg/kg body weight,about 75 mg/kg body weight, about 100 mg/kg body weight, about 125 mg/kgbody weight, about 150 mg/kg body weight, about 175 mg/kg body weight,about 200 mg/kg body weight, about 225 mg/kg body weight, about 250mg/kg body weight, about 275 mg/kg body weight, or about 300 mg/kg bodyweight. Compounds of the present invention may be administered, alone orin combination, in a single daily dose, or the total daily dosage may beadministered in divided dosage of two, three, four, five, or six timesdaily.

The frequency and duration of administration of the acetaminophenprodrug will depend on the condition being treated, the condition of theindividual, and the like. The formulation may be administered to theindividual one or more times, for example, 2, 3, 4, 5, 10, 15, 20, ormore times. The formulation may be administered to the individual, forexample, more than, equal to, or less than once a day, 2 times a day, 3times a day, or more than 3 times a day; or 1-6 times a day, 2-6 times aday, or 4-6 times a day. The formulation may also be administered to theindividual, for example, less than once a day, for example, every otherday, every third day, every week, or less frequently. The formulationmay be administered over a period of days, weeks, or months.

The acetaminophen prodrugs of the invention may be administeredenterally (e.g., orally or rectally), parenterally (e.g., by injection(such as intravenously or intramuscularly), or by inhalation (e.g., asmists or sprays), or topically, in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable caITiers, adjuvants,and vehicles as desired. For example, suitable modes of administrationinclude oral, subcutaneous, transdermal, transmucosal, iontophoretic,intravenous, intraarterial, intramuscular, intraperitoneal, intranasal(e.g., via nasal mucosa), subdural, rectal, gastrointestinal, and thelike, and directly to a specific or affected organ or tissue. Fordelivery to the central nervous system, spinal and epiduraladministration, or administration to cerebral ventlicles, can be used.Topical administration may also involve the use of transdermaladministration such as transdermal patches or iontophoresis devices. Theterm parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques. The acetaminophen prodrugs may be mixed withpharmaceutically acceptable carders, adjuvants, and vehicles appropriatefor the desired route of administration. The route of administration mayvary according to the condition to be treated. Additional methods ofadministration are known in the art.

In some embodiments of the methods, the route of administration is oral.In some embodiments, formulations are suitable for oral administration.acetaminophen prodrugs described for use herein can be administered insolid form, in liquid form, in aerosol form, or in the form of tablets,pills, powder mixtures, capsules, granules, injectables, creams,solutions, suppositories, enemas, colonic irrigations, emulsions,dispersions, food premixes, and in other suitable forms.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose, lactose, or starch. Such dosage forms may also compriseadditional substances other than inert diluents, e.g., lubricatingagents such as magnesium stearate. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents. Tablets andpills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the aii, such as water. Suchformulations may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, cyclodextlins, and sweetening,flavoring, and perfuming agents.

In some embodiments, the acetaminophen prodrug is administeredparenterally intravenously or intramuscularly). Injectable preparations,for example, sterile injectable aqueous or oleaginous suspensions, maybe formulated according o the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin propylene glycol. The sterile injectable preparation may also be asterile powder to be reconstituted using acceptable vehicles prior toadministration. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid may be used in the preparation ofinjectables.

In some embodiments are provided high doses of acetaminophen prodrug ina low volume (e.g., in a low volume of saline). Non-limiting examples ofan effective amount (e.g., for parenteral administration, such asintravenous or intramuscular), include the acetaminophen prodrug at adosage range of from about 20 mg per day to about 8 g per day, or fromabout 60 mg per day to about 6 g, or from about 200 mg per day to about4 g, or from about 300 mg to about 2.6 g per day, or from about 500 mgto about 2 g per day. In some embodiments, the effective amount forparenteral (e.g., intravenous or intramuscular) administration is a dosevolume of about 200 mg to about 5 g, or about 500 mg to about 4 g, orabout 750 mg to about 3 g, or about 1 g to about 2.5 g, or about 1.3 gto about 1.9 g, in about 1 mL to about 30 mL, or about 1 mL to about 25mL, or about 5 mL to about 20 mL, or about 5 mL to about 15 mL or about10 mL to about 15 mL, or about 5 mL to about 10 mL. In some of theseembodiments, the acetaminophen prodrug is administered in a solution ata concentration of about 10 mg/mL to about 1000 mg/mL, or about 25 mg/mLto about 750 mg/mL, or about 50 mg/mL to about 500 mg/mL, or about 75mg/mL to about 400 mg/mL, or about 100 mg/mL to about 300 mg/mL, orabout 150 mg/mL to about 250 mg/mL.

The invention also includes formulations of acetaminophen prodrugsadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The acetaminophen prodrugs of the present invention may also beadministered in the form of liposomes. As is known in the art, liposomesare generally derived from phospholipids or other lipid substances.Liposomes are formed by mono- or multilamellar hydrated liquid crystalsthat are dispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and/or metabolizable lipid capable of forming liposomes maybe used. The present formulations in liposome form can contain, inaddition to an acetaminophen prodrug,stabilizers, preservatives,excipients, and the like. In some embodiments, the lipids are thephospholipids and/or phosphatidyl cholines (lecithins), natural and/orsynthetic. Methods to form liposomes are known in the art, See, forexample, Prescott, Ed., Methods in Cell Biology, Volume XIV, AcademicPress, New York, N.W., p. 33 et seq (1976).

EXAMPLES

The present invention will be understood more readily by reference tothe following examples, which are provided by way of illustration andare not intended to be limiting of the present invention.

Example 1 Synthesis of (4-acetamidophenoxy)methyl dihydrogen phosphateN-(4-(methylthiomethoxy)phenyl)acetamide

To a stirred ash-colored suspension of sodium hydride (1.9 g; 75.49mmol) in hexamethylphosphoramide (HMPA; 25 mL) cooled to 0° C., asolution of acetaminophen (10 g; 66.22 mmol in 35 mL of HMPA) was addedslowly in about 15 minutes. The ash-colored suspension changed to alight-brown clear solution after 15 minutes of stirring. The reactionmixture was stiffed for art additional 20 minutes at 0° C. Thenchloromethyl methyl sulfide (7.67 g; 79.47 mmol) was slowly added to thereaction mixture over about 10 minutes. There was no color change inreaction mixture. The reaction mixture was slowly warmed to roomtemperature and stiffing continued for 3 hr. Rf values of staiiingmaterial and product, in a methanol:dichloromethane solvent system(3:97) on TLC silica gel 60 F₂₅₄ (Merck) detected at A. 254 nm, were0.4, and 0.6, respectively. The reaction mixture was quenched withsaturated ammonium chloride solution (80 mL), extracted with ethylacetate (2×75 mL), the light-brown organic layer separated, dried oversodium sulphate and concentrated. under vacuum. The crude light-browncompound was purified by washing with hexane (3×50 mL), acetonitrile (15mL), diethyl ether (100 mL), and a white solidN-(4-(methylthiomethoxy)phenyl)acetamide product was obtained (3.5 g,25% yield).

(4-acetamidophenoxy)methyl dibenzyl phosphate

To a stirred colorless solution ofN-(4-(methylthiomethoxy)phenyl)acetamide (1.5 g; 7.1 mmol) in THF(stirred with 5 g of activated 4 A molecular sieves for 15 minutes), wasadded a brown colored suspension of N-iodo succinimide (2.6 g; 10.7mmol) followed by addition of dibenzyl phosphate (3.1 g; 11.14 mmol)dissolved in DCM. The resulting brown colored reaction mixture wasstirred at room temperature for 2 hours, Rf values of starting material,dibenzyl phosphate, and product in methanol:dichloromethane solventsystem (3:97) on TLC silica gel 60 F_(2S4) (Merck) detected at A. 254 nmwere 0.6, 0.2, and 0.5, respectively. The reaction mixture was filteredwith Whatman filter paper and the brown filtrate was washed with water(20 mL), extracted with dichloromethane (50 mL), the organic layerseparated, washed with 20% sodium thiosulphate (2×50 mL) and 10% issodium bicarbonate (30 mL), dried with sodium sulphate, and evaporatedto yield the product (1.9 g, 60% yield) as a brown color viscous liquidwhich was purified by column chromatography (silica gel), using 5%methanol in dichloromethane as an eluent.

(4-acetamidophenoxy)methyl dihydrogen phosphate

To a stirred brown colored solution of (4-acetamidophenoxy)methyldibenzyl phosphate (0.4 g 0.9 mmol) in methanol (15 mL), a solution ofPd(OHh (0.2 g) in methanol (10 mL) was added. The reaction mixture wastaken into a glass vessel kept at 60 psi in a Parr hydrogenator at roomtemperature. Rf values of starting material and product in amethanol:dichloromethane solvent system (10:90) on TLC silica gel 60F_(2S4) (Merck) detected at A 254 nm were 0.0, and 0.5, respectively.The catalyst was filtered through celite and washed with methanol (3×5mL). The filtrate was concentrated under vacuum to produce a browncolored gummy mass which was then purified by washing with pentane (2×50mL) and diethyl ether (30 mL) to yield 50 mg (30% yield) of product asan off white solid (melting range: 109-111° C.). ¹H NMR (400 MHz,DMSO-d₆): 8 9.82 (s, 1H), 7.48 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.8Hz), 5.43 (d, 2H, J=10.0 Hz), 2.50 (s, 3H).

Example 2 Synthesis of Sodium (4-acetamidophenoxy)methyl phosphate

To a stirring milky suspension of (4-acetamidophenoxy)methyl dihydrogenphosphate (20 mg; 0.076 mmol) in ethyl acetate (5 mL), a solution ofsodium-2-ethyl hexanoate (25 mg; 0.15 mmol) in ethyl acetate (2 mL) wasadded. The reaction suspension was stirred for 3 h. The milky suspensionturned to a white solid after one hour, which was filtered, washed withethyl acetate (3×15 mL) and ether (3×20 mL) to yield 10 mg (50% yield)of product as a white solid (melting range: 206-209° C.). ¹H NMR (400MHz, DMSO): 8 9.8 (s, 1H), 7.41 (d, 2H, J=10.8 Hz), 6.96 (d, 2H, J=11.6Hz), 5.26 (d, 2H, J=10.4 Hz), 1.97 (s, 3H).

Example 3 Solubility of Acetaminophen Analogs

Solubility of (4-acetamidophenoxy)methyl dihydrogen phosphate and itsdisodium salt is listed in Table 1.

TABLE 1 Solubility of Acetaminophen Prodrugs Solubility Solute Solvent(mg/mL) (4-acetamidophenoxy)methy1 Water 145 dihydrogen phosphate Sodium(4- Water 160 acetamidophenoxy)methyl phosphate

Example 4 In Vitro Conversion of Acetaminophen Prodrug to Acetaminophen

A known amount of acetaminophen prodrug was incubated with human plasmasamples maintained at physiological temperature. Small aliquots weredrawn at predefined time points (0, 5, 10, 15, 20, 25, 30, 40, 60 and120 minutes) and analyzed for acetaminophen content. The experiment wasperformed with two different concentrations of prodrug in pooled humanplasma at 37° C. to determine kinetics of metabolic reaction and whetheror not saturation of enzymatic system involved in conversion of prodrugto acetaminophen drug takes place. It was found that acetaminophenappeared by the time of first sample collection at nominal 0 minutes,and the concentration increased over the duration of 60 minutes, asshown in FIGS. 1 and 2.

Example 5 In Vivo Conversion of Acetaminophen Prodrug to Acetaminophen

Conversion of acetaminophen prodrug to acetaminophen through metabolismin the body was studied in rats. Similar to experimental designdescribed above for in vitro studies, the acetaminophen prodrug wasintravenously administered to the test animal and blood was drawn atpredefined time points. The blood was analyzed for acetaminophen contentor acetaminophen content alone, and the half-life of prodrug wasdetermined.

The pharmacokinetics of acetaminophen and the compound of formula I wereevaluated after intravenous (IV) administration in order to determineresulting plasma acetaminophen concentrations. Acetaminophen andcompound I were dosed on an equimolar basis to provide the same level ofexposure (25 mg/kg) to acetaminophen and to obtain the profile ofcompound of formula I conversion in vivo to acetaminophen. The testanimals were male and female Sprague Dawley (CD® IGS) rats (CharlesRiver Laboratories), 7 to 8 weeks of age, weighing 220 to 270 grams. Therats were serially bled at 7 time points: 5, 15, 30 minutes and 1, 4, 8and 24 hours post-dose. Whole blood samples (300 μL) were collected fromthe tail vein in lithium heparin microcontainers processed to plasma bycentrifugation and plasma was stored frozen at −70° C. until analyzed.Results of plasma analyses for acetaminophen content are shown in FIG. 3and Table 2.

TABLE 2 Summary of calculated pharmacokinetic parameters ofacetaminophen after intravenous administration of compound I to ratsAcetaminophen Prodrug (Acetaminophen) PK Parameter Mean % CV Mean % CVDose (mg/kg) 25 N.A.   25* N.A. Half life (hr) 2.65 43.7     2.12 48.3Tmax (hr) 0.139 62.2     0.083 0.00** Cmax (ng/mL) 26467 22.8 30917 11.5AUCo-s 24300 33.6 21233 20.7 (hr · ng/mL) Clearance 19.5 40.5    20.319.2 (mL/min/kg) Yss (L/kg) 1.48 25.0     1.52 23.1 *molar equivalent of25 mg/kg acetaminophen **all values the same

The invention claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1,wherein the compound is a disodium salt of formula (II):


3. A formulation comprising an effective amount of the compound of claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 4. The formulation of claim 3, wherein thepharmaceutically acceptable carrier is saline.
 5. The formulation ofclaim 3, further comprising a compound selected from the groupconsisting of an opioid, non-steroidal anti-inflammatory drug (NSAID),benzodiazepine, and barbiturate.
 6. The formulation of claim 3, furthercomprising a compound selected from the group consisting of codeine,morphine, hydrocodone, hydromorphone, levorphanol, aspirin, ketorolac,ibuprofen, naproxen, caffeine, tramadol, dextropropoxyphene,methylhexital, diazepam, lorazepam, midazolam, propoxyphene, ketoprofen,flurbiprofen, etodolac, diclofenac, misoprostol, meloxicam, piroxicam,doxylamine, pamabrom, carisoprodol, and butalbital.
 7. A substantiallypure form of the compound of claim 1, or a pharmaceutically acceptablesalt thereof.
 8. A method of treating pain, fever, ischemic injury, orneural injury comprising administering to an individual an effectiveamount of the compound of claim 1, or a pharmaceutically acceptable saltthereof.
 9. The method of claim 8, wherein the method comprisesadministering a formulation comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. The method according to claim 8, wherein thecompound, or a pharmaceutically acceptable salt thereof, is administeredparenterally.
 11. The method according to claim 10, wherein thecompound, or a pharmaceutically acceptable salt thereof, is administeredintravenously.
 12. The method according to claim 10, wherein thecompound, or a pharmaceutically acceptable salt thereof, is administeredintramuscularly.
 13. The method according to claim 10, wherein thecompound, or a pharmaceutically acceptable salt thereof, is administeredsubcutaneously.
 14. The method according to claim 8, wherein the dosageof the compound, or a pharmaceutically acceptable salt thereof, is about300 mg to about 2.6 g.
 15. The method according to claim 14, wherein thedosage of the compound, or a pharmaceutically acceptable salt thereof,is about 1.3 g to about 1.9 g.
 16. The method according to claim 14,wherein the volume of the dosage is about 1 mL to about 25 mL.
 17. Themethod according to claim 16, wherein the volume of the dosage is about10 mL to about 20 mL.
 18. The method according to claim 16, wherein thevolume of the dosage is about 1 mL to about 10 mL.
 19. The methodaccording to claim 16, wherein the volume of the dosage is about 5 mL toabout 10 mL.
 20. The method according to claim 14, wherein the dosage isadministered more than once a day.
 21. The method according to claim 14,wherein the dosage is administered once every other day or less.
 22. Theformulation of claim 3, wherein the formulation is a low volume/highconcentration formulation.
 23. The formulation of claim 3, wherein theformulation comprises a disodium salt of formula (II):


24. The method of claim 8, wherein the method comprises administering toan individual an effective amount of a disodium salt of formula (II):